Specific delivery of chemotherapeutic agents to desired target sites with a minimum of systemic side effects constitutes one of the ongoing challenges of chemotherapy. Chemical approaches to such "targeting" depend on biochemical differences between cells, but such differences are more quantitative than qualitative. Thus the drugs administered have activity in areas of the body where activity is not desired. An alternative to chemically mediated targeting is the entrapment of a chemotherapeutic agent in a carrier which can mechanically effect distribution of the drug.
In 1974, Kramer proposed albumin microspheres as vehicles for achieving specificity in drug delivery. J. Pharm. Sci., 63, 1646-1647 (Oct. 1974). Entrapment of the anti-cancer drug mercaptopurine was demonstrated but not specifity of delivery. Kramer did suggest that intravenous administration of the microspheres might result in preferential uptake in such tissues as liver or bone marrow due to non-specific phagocytosis with a possible reduction in required total doses and thereby less systemic side effects. This would still be far short of the desired objective since only diseases of the reticuloendothelial system would be affected. Local compartmentalization of water soluble chemotherapeutic agents at desired target sites, if it could be achieved, would permit administration of much lower doses by largely eliminating systemic dilution of the drug. In addition, many of the adverse side effects that are often the result of systemic distribution could be eliminated. Unfortunately, prior to the present invention, no system of administration has been provided which can effectively deliver therapeutic agents intravascularly to a selected site. Such a system also has value for administration of diagnostic agents.
Freeman et al proposed in 1960 that magnetic iron particles might be used as a means for transporting radiation or some healing chemical to a particular spot in the body, the particles being magnetically directed. J. App. Phys., Supp. Vol. 31, 404S-405S (May 1960). It was proposed that the iron particles could be alloyed with the proper choice of radioactive element, or that they could be coated with an adsorbed layer of a therapeutic agent. Later Meyers et al suggested the use of carbonyl iron particles as vehicles for site specific delivery of chemotherapeutic agents. Amer. J. Roentg., 90, 1068-1077 (Nov. 1963). Magnetic iron particles of 1 to 3 microns in diameter were shown to be localized in the vessels or gastrointestinal tract of dogs with a magnetic field of approximately 5,000 gauss. It appeared that some of the particles had been pulled through the artery into the tissues by the magnetic field. However, the surface properties of magnetic particles, such as carbonyl iron, lead to irreversible intravascular clumping upon exposure to a magnetic field unless they are coated with electronegative polymer such as albumin. Nakamura et al; J. App. Phys. 42, 1320-1324 (1971). Alksne et al, Surgery, 60, 212 (1966) employed carbonyl iron microspheres to occlude intracranial aneurysms in both animals and humans, thereby utilizing the "clumping" phenomenon for a therapeutic purpose. In 1973, Mosso et al reported an improved method for clumping particles by the use of ferromagnetic silicon which they used for selective vascular occlusion and subsequent necrosis of tumors in humans Ann. Surg., 178:5, 663 (1973). The prior art does not provide a solution to the problem of how accurate magnetic direction of intravascularly administered magnetic particles can be obtained, nor to the equally difficult problem of how sufficient loading of the chemotherapeutic agent per particle can be obtained.
Microcapsules containing magnetic particles are disclosed in U.S. Pat. No. 2,971,916. Microcapsules of 3 to 150 microns in diameter are formed by coacervation, the capsules having walls of hardened organic colloid material enclosing an oily liquid containing a dispersion of magnetic powder. No medical application is suggested, the capsules being indicated as useful for imprinting of data on record sheets.